The present invention pertains in general to antigens associated with tumors and uses therefor, and in particular to regression-associated antigens (RAAs) and uses therefor.
During the past decade much effort has focused on the development of polyclonal and monoclonal antibodies for diagnosis and treatment of cancers. In almost all cases the immunogens have been intact tumor cells or membrane proteins obtained from the cells in order to obtain antibodies directed against tumor cell components. Early work in this field allowed the identification of interesting but not therapeutically useful onco-fetal antigens and blood group antigens [Springer, Science, 224, 1198 (1984)]expressed on malignant cells and shed into the bloodstream in some instances. More recently, antigens associated with tumor cells have been identified by immunoblotting methods. Du Bois et al., J. Immunol. Methods, 63, 7 (1983). Monoclonal antibodies reactive with the surface of human breast carcinoma cells have been generated and characterized. Schlom et al., Cancer, 54 (11 suppl.), 2777-2794 (1984). The immunogens used were membrane-enriched fractions of metastatic carcinoma lesions. One monoclonal antibody reacted with a 220,000 to 400,000 dalton high-molecular weight glycoprotein complex found in 50% of human mammary carcinomas and 80% of human colon carcinomas. A number of equally intriguing monoclonal antibodies reactive with tumor-associated antigens on the surfaces of other human cancers including ovarian, pancreatic and intestinal malignancies have thus been obtained. See the Proceedings of the UCLA Symposium on Monoclonal Antibodies and Cancer Therapy, Reisfeld et al., eds., A. R. Liss, Inc., New York (1985).
The antibodies, monoclonal and polyclonal, described to date have been directed against determinants of human tumor cell antigens which may elicit an immune response in test animals chosen for the production of tumor-specific antibodies. It is not known whether patients harboring tumors or treated with specific and/or nonspecific immune stimulants produce antibodies against these antigenic determinants. Therefore, the relevance of such antibodies in mediating regression of tumors in patients is unclear. Passive transfer of such antibodies generated in other animals into patients has met with only a limited success. Lowder et al., Western J. Med. 143, 810, (1985).
An interesting clinical approach toward active immunotherapy of tumors involves the generalized stimulation of the patient's own immune system using non-specific stimulants such as components of the walls of two bacterial cells, Mycobacterium bovis (BCG strain) and Corynebacterium parvum (C. parvum), or "detoxified" bacterial endotoxin. In parallel, biological response modifiers such as interleukin 2 have been used to induce activation of the immune system and cause tumor cell destruction. Mule et al., J. Immunol., 135, 646 (1985); and Rosenberg et al., New Engl. J. Med., 313, 1485 (1985).
Concurrently with these efforts attempts have been made to immunize cancer patients with allogenic tumor cell preparations (tumor cell lines obtained from a similar histopathologic tumor from a different patient) as vaccines. This would be expected to specifically stimulate the patient's own immune system to possible unique antigenic structures present on the particular malignant cell type and thus induce tumor regression. Lachman et al. Br. J. Cancer, 51, 415-417 (1985); Wallacket al., Surgery, 96, 791-800 (1984). Active specific immunotherapy has also been attempted by systematically injecting autochthonous (cells derived from the tumor mass of the same patient) tumor cell vaccines intradermally or subcutaneously. Laucius et al., Cancer, 40, 2091 (1977).